POPular GUILTY pilot: Genotype-guided clopidogrel monotherapy

Dual antiplatelet therapy (DAPT) consisting of aspirin and a P2Y12 inhibitor is
the cornerstone of treatment in patients with acute coronary syndrome (ACS) and
those receiving coronary stent implantation, reducing the risk of stent
thrombosis, myocardial infarction and stroke. [1,2] However, the need for
aspirin is currently challenged as both technical (e.g. stent design and
interventional technique) and pharmaceutical (e.g. more potent P2Y12
inhibitors) advancements reduced atherothrombotic complications and DAPT is
associated with bleeding complications.[3]

Several randomized controlled trials concluded that single antiplatelet therapy
(SAPT) with a P2Y12 inhibitor reduces major and clinically relevant non-major
bleeding complications and is non-inferior to DAPT with respect to ischemic
events, in both acute and chronic coronary syndrome patients.[4-8] However,
P2Y12-inhibitor monotherapy was preceded by a 1-3 month period of DAPT in all
these trials. The recent Acetyl Salicylic Elimination Trial (ASET) pilot study
was the first trial completely omitting aspirin after successful percutaneous
coronary intervention (PCI).[9] In the 201 patients treated with prasugrel
monotherapy, no stent thrombosis occurred during a 4-month follow-up period.

Whether complete omission of aspirin reduces the rate of major or minor
bleeding while maintaining non-inferiority to the current standard of care
(DAPT) with respect to ischemic event rate in NSTE-ACS patients undergoing PCI,
is currently investigated in The Less Bleeding by Omitting Aspirin in
Non-ST-segment Elevation Acute Coronary Syndrome Patients (LEGACY) trial. This
open-label, multicenter randomized controlled trial randomizes NSTE-ACS
patients undergoing PCI in a 1:1 ratio to the intervention group receiving
P2Y12-inhibitor monotherapy (ticagrelor or prasugrel) for 12 months or the
standard group receiving DAPT for 12 months.

Previous studies showed that the P2Y12-inhibitors prasugrel and ticagrelor
reach more potent and reliable platelet inhibition than clopidogrel, reducing
the incidence of myocardial infarction and definite or probable stent
thrombosis with 16-24% and 25-52%, respectively.[10,11] The higher incidence of
ischemic events in patients using clopidogrel may, however, be explained by the
great interindividual variability in P2Y12 inhibition. Clopidogrel is a prodrug
requiring bioactivation into its active metabolite, which irreversibly inhibits
P2Y12 receptors on platelets and therewith platelet aggregation.[12] Various
defective polymorphisms of the CYP2C19 gene have been found, encoding the
CYP2C19 enzyme responsible for the bioactivation by hepatic cytochrome P450
enzymes.[13] Approximately 30% of Caucasian patients carry at least one
loss-of-function (LOF) allele such as CYP2C19*2 or CYP2C19*3, resulting in high
on-treatment platelet reactivity and an increased risk of atherothrombotic
events.[12,14-16 In patients without LOF alleles, however, clopidogrel has
similar efficacy in prevention of ischemic complications to ticagrelor and
prasugrel.[17-20]

In addition, the more potent P2Y12 inhibitors are associated with a significant
increase in bleeding complications. When compared to clopidogrel, patients
receiving prasugrel had a 32% higher incidence of TIMI major hemorrhage,
including both life-threatening and fatal bleeding, and patients using
ticagrelor had a 25% increase in non-CABG related major TIMI bleeding. [10,11]

This single-centre, single-arm pilot study will explore the feasibility and
safety of genotype-guided clopidogrel monotherapy in CYP2C19 extensive
metabolizers presenting with NSTE-ACS and undergoing successful PCI. We
hypothesize that genotype-guided clopidogrel monotherapy is safe with regards
to bleeding and ischemic endpoints in Non-ST-Segment Elevation Acute Coronary
Syndrome Patients undergoing successful PCI.

REFERENCES
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2. Collet J-P, Thiele H, Barbato E, et al. 2020 ESC Guidelines for the
management of acute coronary syndromes in patients presenting without
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nucleo

This study has been transitioned to CTIS with ID 2024-518464-12-00 check the CTIS register for the current data.

The primary efficacy endpoint is to assess ischemic risk of genotype-guided
clopidogrel monotherapy during the first 6 months following successful PCI in
NSTE-ACS patients.

The primary safety endpoint is to assess bleeding risk of genotype-guided
clopidogrel monotherapy during the first 6 months following successful PCI in
NSTE-ACS patients.

Secondary objective
The secondary endpoints include the individual components of the primary safety
and efficacy endpoints (at 3 and 6 months).

This is a single-center, single-arm, open-label, proof-of-concept trial
assessing the safety and efficacy of genotype-guided clopidogrel monotherapy
following successful PCI in NSTE-ACS patients. The study design is illustrated
in Figure 1 in the protocol.

In this pilot study, patients presenting with NSTE-ACS who have undergone
successful PCI will be enrolled in case of CYP2C19 wildtype genotype. Patients
will be treated with clopidogrel monotherapy.

After 1, 3, and 6 months (+/- 2 weeks) after hospital discharge, patients will
be contacted by phone to discuss clinical events, adverse events and
self-reported adherence to medication. In addition, medical files will be
reviewed.

Treatment before PCI:
• Patients will be treated with a loading dose of 60 mg prasugrel, 180 mg
ticagrelor or 600mg clopidogrel at least 2 hours prior to coronary angiography.

Treatment after PCI:
• Patients will be treated with 75mg clopidogrel once daily for 6 months
• After 6 months, medical regimen is at the discretion of the treating
physician.

Patients will be contacted by phone at 1, 3, and 6 months after successful PCI.
Omitting aspirin may lead to a reduction in (major) bleeding events. However,
it is unknown whether omitting aspirin affects the risk of ischemic events.